The objective of this proposal is to identify the most promising vasodilator substances for the treatment of intestinal ischemic states. These conditions are often fatal and are marked by ischemia, tissue hypoxia and necrosis, most severe in the mucosal of the gut. Current therapy is ineffective. The vasodilator agents to be used will be infused via a catheter placed in the superior mesenteric artery for direct intraarterial infusion. In the proposed study we will use the anesthetized dog as our model, testing agents in the normotensive animal and in states of experimental intestinal vaso-constriction induced by hemorrhage, endotoxin shock, ouabain and vasopressin. We will measure superior mesenteric artery blood flow, systemic arterial and portal venous pressures, systemic arterial and mesenteric venous blood oxygen content, Rb86 clearance by the gut, Cr51 labelled microsphere distribution in the wall of the gut, and mucosal ATP, cyclic AMP and cyclic GMP content. These measurements will permit calculation of mesenteric vascular resistance and intestinal oxygen consumption, and will yield insights about the microcirculatory locus of drug action, the effect of drugs on the nutrient circulation, the effect on mucosal blood flow and oxygen uptake, and the effect upon tissue energetics. The most promising vasodilator candidates should show persistent and selective reversal of intestinal mucosal ischemia and hypoxia without imposing adverse effects upon the rest of the circulation. Agents to be tested include such naturally occurring substances as gastrointestinal hormones (e.g., glucagon and V.I.P.), tissue substances (e.g., prostaglandin E1 and bradykinin) and neurotransmitters (e.g., acetylcholine).